{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T09:24:31Z","timestamp":1787563471578,"version":"build-2736575974"},"reference-count":27,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2019,3,3]],"date-time":"2019-03-03T00:00:00Z","timestamp":1551571200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS073873"],"award-info":[{"award-number":["R01 NS073873"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01 NS104022"],"award-info":[{"award-number":["R01 NS104022"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002160","name":"Jain Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100002160","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2019,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      Dysferlin is a large transmembrane protein that functions in critical processes of membrane repair and vesicle fusion. Dysferlin\u2010deficiency due to mutations in the dysferlin gene leads to muscular dystrophy (Miyoshi myopathy (\n                      <jats:styled-content style=\"fixed-case\">MM<\/jats:styled-content>\n                      ), limb girdle muscular dystrophy type 2B (\n                      <jats:styled-content style=\"fixed-case\">LGMD<\/jats:styled-content>\n                      2B), distal myopathy with anterior tibial onset (\n                      <jats:styled-content style=\"fixed-case\">DMAT<\/jats:styled-content>\n                      )), typically with early adult onset. At least 416 pathogenic dysferlin mutations are known, but for approximately 17% of patients, one or both of their pathogenic variants remain undefined following standard exon sequencing methods that interrogate exons and nearby flanking intronic regions but not the majority of intronic regions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We sequenced\n                      <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>\n                      from myogenic cells to identify a novel dysferlin pathogenic variant in two affected siblings that previously had only one disease\u2010causing variant identified. We designed antisense oligonucleotides (\n                      <jats:styled-content style=\"fixed-case\">AON<\/jats:styled-content>\n                      s) to bypass the effects of this mutation on\n                      <jats:styled-content style=\"fixed-case\">RNA<\/jats:styled-content>\n                      splicing.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identified a new pathogenic point mutation deep within dysferlin intron 50i. This intronic variant causes aberrant\n                      <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content>\n                      splicing and inclusion of an additional pseudoexon (\n                      <jats:styled-content style=\"fixed-case\">PE<\/jats:styled-content>\n                      , we term\n                      <jats:styled-content style=\"fixed-case\">PE<\/jats:styled-content>\n                      50.1) within the mature dysferlin\n                      <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content>\n                      .\n                      <jats:styled-content style=\"fixed-case\">PE<\/jats:styled-content>\n                      50.1 inclusion alters the protein sequence, causing premature translation termination. We identified this mutation in 23 dysferlinopathy patients (seventeen families), revealing it to be one of the more prevalent dysferlin mutations. We used\n                      <jats:styled-content style=\"fixed-case\">AON<\/jats:styled-content>\n                      \u2010mediated exon skipping to correct the aberrant\n                      <jats:styled-content style=\"fixed-case\">PE<\/jats:styled-content>\n                      50.1 splicing events in\u00a0vitro, which increased normal\n                      <jats:styled-content style=\"fixed-case\">mRNA<\/jats:styled-content>\n                      production and significantly restored dysferlin protein expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Interpretation<\/jats:title>\n                    <jats:p>\n                      Deep intronic mutations can be a common underlying cause of dysferlinopathy, and importantly, could be treatable with\n                      <jats:styled-content style=\"fixed-case\">AON<\/jats:styled-content>\n                      \u2010based exon\u2010skipping strategies.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/acn3.738","type":"journal-article","created":{"date-parts":[[2019,3,3]],"date-time":"2019-03-03T21:35:01Z","timestamp":1551648901000},"page":"642-654","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Correction of pseudoexon splicing caused by a novel intronic dysferlin mutation"],"prefix":"10.1002","volume":"6","author":[{"given":"Janice A.","family":"Dominov","sequence":"first","affiliation":[{"name":"Department of Neurology University of Massachusetts Medical School Worcester Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00d6zg\u00fcn","family":"Uyan","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Massachusetts Medical School Worcester Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diane","family":"McKenna\u2010Yasek","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Massachusetts Medical School Worcester Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Babi Ramesh Reddy","family":"Nallamilli","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Emory University School of Medicine Atlanta Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginie","family":"Kergourlay","sequence":"additional","affiliation":[{"name":"Marseille Medical Genetics \u2010 Translational Neuromyology Aix\u2010Marseille Univ INSERM MMG Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Bartoli","sequence":"additional","affiliation":[{"name":"Marseille Medical Genetics \u2010 Translational Neuromyology Aix\u2010Marseille Univ INSERM MMG Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Levy","sequence":"additional","affiliation":[{"name":"Marseille Medical Genetics \u2010 Translational Neuromyology Aix\u2010Marseille Univ INSERM MMG Marseille France"},{"name":"D\u00e9partement de G\u00e9n\u00e9tique M\u00e9dicale APHM H\u00f4pital Timone Enfants Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Hudson","sequence":"additional","affiliation":[{"name":"Northern Molecular Genetics Service Newcastle upon Tyne United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresinha","family":"Evangelista","sequence":"additional","affiliation":[{"name":"Newcastle University John Walton Centre for Muscular Dystrophy Research MRC Centre for Neuromuscular Diseases Institute of Genetic Medicine Newcastle upon Tyne United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanns","family":"Lochmuller","sequence":"additional","affiliation":[{"name":"Newcastle University John Walton Centre for Muscular Dystrophy Research MRC Centre for Neuromuscular Diseases Institute of Genetic Medicine Newcastle upon Tyne United Kingdom"},{"name":"Department of Neuropediatrics and Muscle Disorders Faculty of Medicine Medical Center\u2013University of Freiburg Freiburg Germany"},{"name":"Centro Nacional de An\u00e1lisis Gen\u00f3mico (CNAG\u2010CRG) Center for Genomic Regulation Barcelona Institute of Science and Technology (BIST) Barcelona Catalonia Spain"},{"name":"Children's Hospital of Eastern Ontario Research Institute University of Ottawa Ottawa Canada"},{"name":"Division of Neurology Department of Medicine The Ottawa Hospital Ottawa Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Krahn","sequence":"additional","affiliation":[{"name":"Marseille Medical Genetics \u2010 Translational Neuromyology Aix\u2010Marseille Univ INSERM MMG Marseille France"},{"name":"D\u00e9partement de G\u00e9n\u00e9tique M\u00e9dicale APHM H\u00f4pital Timone Enfants Marseille France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Rufibach","sequence":"additional","affiliation":[{"name":"Jain Foundation, Inc. Seattle Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madhuri","family":"Hegde","sequence":"additional","affiliation":[{"name":"Department of Human Genetics Emory University School of Medicine Atlanta Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"suffix":"Jr","given":"Robert H.","family":"Brown","sequence":"additional","affiliation":[{"name":"Department of Neurology University of Massachusetts Medical School Worcester Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,3,3]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/1682"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/1689"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000089"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.172"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1089\/hum.2017.062"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0854.2007.00573.x"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2007.07.001"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.06-7659com"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.21166"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-009-0632-y"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2008.070327"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nmd.2009.08.004"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.448589"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.10080"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.24195"},{"key":"e_1_2_8_17_1","doi-asserted-by":"crossref","first-page":"302","DOI":"10.4103\/aian.AIAN_129_17","article-title":"Detection of dysferlin gene pathogenic variants in the indian population in patients predicted to have a dysferlinopathy using a blood\u2010based monocyte assay and clinical algorithm: a model for accurate and cost\u2010effective diagnosis","volume":"20","author":"Dastur RS","year":"2017","journal-title":"Ann Indian Acad Neurol"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22015"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.96"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkp215"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1073774"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2016.04.007"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-017-1809-4"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-017-1820-9"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aal5209"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep39094"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.267"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000204358.89303.81"}],"container-title":["Annals of Clinical and Translational Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Facn3.738","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.738","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/acn3.738","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/acn3.738","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,10]],"date-time":"2023-09-10T16:19:28Z","timestamp":1694362768000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/acn3.738"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,3,3]]},"references-count":27,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2019,4]]}},"alternative-id":["10.1002\/acn3.738"],"URL":"https:\/\/doi.org\/10.1002\/acn3.738","archive":["Portico"],"relation":{},"ISSN":["2328-9503","2328-9503"],"issn-type":[{"value":"2328-9503","type":"print"},{"value":"2328-9503","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,3,3]]},"assertion":[{"value":"2018-04-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-01-21","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-03-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}